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  • Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000)
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-17
    Martin Schrappe; Kirsten Bleckmann; Martin Zimmermann; Andrea Biondi; Anja Möricke; Franco Locatelli; Gunnar Cario; Carmelo Rizzari; Andishe Attarbaschi; Maria Grazia Valsecchi; Claus R. Bartram; Elena Barisone; Felix Niggli; Charlotte Niemeyer; Anna Maria Testi; Georg Mann; Ottavio Ziino; Beat Schäfer; Renate Panzer-Grümayer; Rita Beier; Rosanna Parasole; Gudrun Göhring; Wolf-Dieter Ludwig; Fiorina Casale; Paul-Gerhardt Schlegel; Giuseppe Basso; Valentino Conter

    Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% (P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% (P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% (P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively (P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.

    更新日期:2017-11-19
  • Impact of Prognostic Discussions on the Patient-Physician Relationship: Prospective Cohort Study
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-17
    Joshua J. Fenton; Paul R. Duberstein; Richard L. Kravitz; Guibo Xing; Daniel J. Tancredi; Kevin Fiscella; Supriya Mohile; Ronald M. Epstein

    Purpose Some research has suggested that discussion of prognosis can disrupt the patient-physician relationship. This study assessed whether physician discussion of prognosis is associated with detrimental changes in measures of the strength of the patient-physician relationship. Methods This was a longitudinal cohort study of 265 adult patients with advanced cancer who visited 38 oncologists within community- and hospital-based cancer clinics in Western New York and Northern California. Prognostic discussion was assessed by coding transcribed audio-recorded visits using the Prognostic and Treatment Choices (PTCC) scale and by patient survey at 3 months after the clinic visit. Changes in the strength of the patient-physician relationship were computed as differences in patient responses to The Human Connection and the Perceived Efficacy in Patient-Physician Interactions scales from baseline to 2 to 7 days and 3 months after the clinic visit. Results Prognostic discussion was not associated with a temporal decline in either measure. Indeed, a one-unit increase in PTCC during the audio-recorded visit was associated with improvement in The Human Connection scale at 2 to 7 days after the visit (parameter estimate, 0.10; 95% CI, −0.02 to 0.23) and 3 months after the visit (parameter estimate, 0.18; 95% CI, 0.02 to 0.35) relative to baseline. Standardized effect sizes (SES) associated with an increase of two standard deviations in the PTCC at each time point were consistent with small beneficial effects (SES, 0.14 [95% CI, −0.02 to 0.29] at 2 to 7 days; SES, 0.24 [95% CI, 0.02 to 0.45] at 3 months), and lower bounds of CIs indicated that substantial detrimental effects of prognostic discussion were unlikely. Conclusion Prognostic discussion is not intrinsically harmful to the patient-physician relationship and may even strengthen the therapeutic alliance between patients and oncologists.

    更新日期:2017-11-19
  • Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-20
    Edward S. Kim; Suanna S. Bruinooge; Samantha Roberts; Gwynn Ison; Nancy U. Lin; Lia Gore; Thomas S. Uldrick; Stuart M. Lichtman; Nancy Roach; Julia A. Beaver; Rajeshwari Sridhara; Paul J. Hesketh; Andrea M. Denicoff; Elizabeth Garrett-Mayer; Eric Rubin; Pratik Multani; Tatiana M. Prowell; Caroline Schenkel; Marina Kozak; Jeff Allen; Ellen Sigal; Richard L. Schilsky

    Purpose The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention’s benefit-risk profile. Methods ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community. Results Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low. Conclusion To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.

    更新日期:2017-11-17
  • Re-Evaluating Eligibility Criteria for Oncology Clinical Trials: Analysis of Investigational New Drug Applications in 2015
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-20
    Susan Jin; Richard Pazdur; Rajeshwari Sridhara

    Clinical trial eligibility criteria are necessary to define the patient population under study and improve trial safety. However, there are concerns that eligibility criteria for cancer clinical trials are too restrictive and limit patient enrollment in clinical trials. Recently, there have been initiatives to re-examine and modernize eligibility criteria for oncology clinical trials. To assess current eligibility requirements for cancer clinical trials, we have conducted a comprehensive review of eligibility criteria for commercial investigational new drug clinical trial applications submitted to the US Food and Drug Administration Office of Hematology and Oncology Products in 2015. Our findings suggest that eligibility criteria for current cancer clinical trials tend to narrowly define the study population and limit the study to lower-risk patients, which may not be reflective of the greater patient population outside of the study. We discuss potential areas for expanding eligibility criteria to include more patients in clinical trials and design options for clinical trials incorporating expanded eligibility criteria. The broadening of clinical trial eligibility criteria can be considered to better reflect the real-world patient population, improve clinical trial participation, and increase patient access to new investigational treatments.

    更新日期:2017-11-17
  • Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-20
    Stuart M. Lichtman; R. Donald Harvey; Marie-Anne Damiette Smit; Atiqur Rahman; Michael A. Thompson; Nancy Roach; Caroline Schenkel; Suanna S. Bruinooge; Patricia Cortazar; Dana Walker; Louis Fehrenbacher

    Purpose Patients with organ dysfunction, prior or concurrent malignancies, and comorbidities are often excluded from clinical trials. Excluding patients on the basis of these factors results in clinical trial participants who are healthier and younger than the overall population of patients with cancer. Methods ASCO and Friends of Cancer Research established a multidisciplinary working group that included experts in trial design and conduct to examine how eligibility criteria could be more inclusive. The group analyzed current eligibility criteria; conducted original data analysis; considered safety concerns, potential benefits, research, and potential hurdles of this approach through discussion; and reached consensus on recommendations regarding updated eligibility criteria that prioritize inclusiveness without compromising patient safety. Results If renal toxicity and clearance are not of direct treatment-related concern, then patients with lower creatinine clearance values of > 30 mL/min should be included in trials. Inclusion of patients with mild to moderate hepatic dysfunction may be possible when the totality of the available nonclinical and clinical data indicates that inclusion is safe. Ejection fraction values should be used with investigator assessment of a patient’s risk for heart failure to determine eligibility. Patients with laboratory parameters out of normal range as a result of hematologic disease should be included in trials. Measures of patient functional status should be included in trials to better assess fit versus frail patients. Conclusion Expanding inclusion of these patients will increase the number and diversity of patients in clinical trials and result in a more appropriate population of patients.

    更新日期:2017-11-17
  • Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Brain Metastases Working Group
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-20
    Nancy U. Lin; Tatiana Prowell; Antoinette R. Tan; Marina Kozak; Oliver Rosen; Laleh Amiri-Kordestani; Julia White; Joohee Sul; Louise Perkins; Katherine Beal; Richard Gaynor; Edward S. Kim

    Purpose Broadening trial eligibility to improve accrual and access and to better reflect intended-to-treat populations has been recognized as a priority. Historically, patients with brain metastases have been understudied, because of restrictive eligibility across all phases of clinical trials. Methods In 2016, after a literature search and series of teleconferences, a multistakeholder workshop was convened. Our working group focused on developing consensus recommendations regarding the inclusion of patients with brain metastases in clinical trials, as part of a broader effort that encompassed minimum age, HIV status, and organ dysfunction. The working group attempted to balance the needs of protecting patient safety, facilitating access to investigational therapies, and ensuring trial integrity. On the basis of input at the workshop, guidelines were further refined and finalized. Results The working group identified three key populations: those with treated/stable brain metastases, defined as patients who have received prior therapy for their brain metastases and whose CNS disease is radiographically stable at study entry; those with active brain metastases, defined as new and/or progressive brain metastases at the time of study entry; and those with leptomeningeal disease. In most circumstances, the working group encourages the inclusion of patients with treated/stable brain metastases in clinical trials. A framework of key considerations for patients with active brain metastases was developed. For patients with leptomeningeal disease, inclusion of a separate cohort in both early-phase and later-phase trials is recommended, if CNS activity is anticipated and when relevant to the specific disease type. Conclusion Expanding eligibility to be more inclusive of patients with brain metastasis is justified in many cases and may speed the development of effective therapies in this area of high clinical need.

    更新日期:2017-11-17
  • Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-20
    Thomas S. Uldrick; Gwynn Ison; Michelle A. Rudek; Ariela Noy; Karl Schwartz; Suanna Bruinooge; Caroline Schenkel; Barry Miller; Kieron Dunleavy; Judy Wang; Jerome Zeldis; Richard F. Little

    Purpose People with HIV are living longer as a result of effective antiretroviral therapy. Cancer has become a leading cause of morbidity and mortality in this patient population. However, studies of novel cancer therapeutics have historically excluded patients with HIV. Critical review of eligibility criteria related to HIV is required to accelerate development of and access to effective therapeutics for HIV-infected patients with cancer and make studies more generalizable to this patient population. Methods From January through April 2016, the HIV Working Group conducted a series of teleconferences; a review of 46 New Drug Applications from registration studies of unique agents studied in adults with cancer that led to the initial US Food and Drug Administration approval of that agent from 2011 to 2015; and a review of HIV-related eligibility criteria from National Cancer Institute–sponsored studies. Results were discussed and refined at a multistakeholder workshop held May 12, 2016. The HIV Working Group developed recommendations for eligibility criteria that focus on pharmacologic and immunologic considerations in this patient population and that balance patient safety, access to appropriate investigational agents, and study integrity. Results Exclusion of patients with HIV remains common in most studies of novel cancer agents. Models for HIV-related eligibility criteria in National Cancer Institute–sponsored studies are instructive. HIV infection itself should no longer be an exclusion criterion for most studies. Eligibility criteria related to HIV infection that address concurrent antiretroviral therapy and immune status should be designed in a manner that is appropriate for a given cancer. Conclusion Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need.

    更新日期:2017-11-17
  • Modernizing Clinical Trial Eligibility: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Minimum Age Working Group
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-20
    Lia Gore; S. Percy Ivy; Frank M. Balis; Eric Rubin; Katherine Thornton; Martha Donoghue; Samantha Roberts; Suanna Bruinooge; Jennifer Ersek; Nancy Goodman; Caroline Schenkel; Gregory Reaman

    Purpose Children have historically been excluded from first-in-human studies of promising new cancer drugs and later phase adult clinical trials. Delays in evaluation may result in off-label use without dosing information as the only access to new drugs. A multistakeholder workshop was convened in May 2016 by ASCO and Friends of Cancer Research to identify opportunities for when it would be scientifically appropriate to expand trial eligibility to include children younger than age 18 years in first-in-human and other adult cancer clinical trials. Methods This group convened experts from academia, government, and industry to review barriers to enrolling children and adolescents in oncology clinical trials. We evaluated the historical context, published literature, regulatory considerations, and myriad risks and benefits associated with lowering the age of enrollment on oncology clinical trials. Results We conclude that many of the historical concerns about including children early in oncology clinical trials do not apply in the current scientific and clinical environment of pediatric oncology and drug development; we provide specific recommendations for how the inclusion of children in early-phase investigational cancer drug trials might be accomplished. Automatic inclusion of pediatric patients is appropriate in early-phase trials that assess dose, safety, and pharmacokinetics in a variety of tumor types and later phase trials that assess efficacy in a specific disease that spans adult and pediatric populations. Conclusion Including children in appropriately designed adult clinical oncology trials is feasible and can be done in a way that enhances their access to these agents without compromising safety or development strategies.

    更新日期:2017-11-17
  • Role of Patient Coping Strategies in Understanding the Effects of Early Palliative Care on Quality of Life and Mood
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-15
    Joseph A. Greer; Jamie M. Jacobs; Areej El-Jawahri; Ryan D. Nipp; Emily R. Gallagher; William F. Pirl; Elyse R. Park; Alona Muzikansky; Juliet C. Jacobsen; Vicki A. Jackson; Jennifer S. Temel

    PurposeThe early integration of oncology and palliative care (EIPC) improves quality of life (QOL) and mood for patients with advanced cancer. However, the mechanisms by which EIPC benefits these outcomes remain unclear. We therefore examined whether EIPC improved patients’ coping strategies and if changes in coping accounted for intervention effects on QOL and depressive symptoms.Patients and MethodsFor this secondary analysis of an EIPC trial, we examined data from 350 patients with newly diagnosed incurable lung or GI cancer. Participants completed assessments of QOL (Functional Assessment of Cancer Therapy–General), depressive symptoms (Patient Health Questionnaire–9), and coping (Brief COPE) at baseline and 24 weeks. We used linear regression to test intervention effects on use of coping strategies and mediation regression models with bias-corrected bootstrapping to examine whether improvements in coping mediated the effects of early palliative care on patient-reported outcomes.ResultsCompared with usual oncology care, EIPC significantly increased patient use of approach-oriented coping strategies (B = 1.09; SE = 0.44; P = .01) and slightly reduced use of avoidant strategies (B = −0.44; SE = 0.23; P = .06) from baseline to 24 weeks. Also, the increased use of approach-oriented coping and reduction in avoidant coping were associated with higher QOL and lower depressive symptoms at 24 weeks. The positive changes in approach-oriented coping, but not avoidant coping, significantly mediated the effects of EIPC on QOL (indirect effect, 1.27; 95% CI, 0.33 to 2.86) and depressive symptoms (indirect effect, −0.39; 95% CI, −0.87 to −0.08).ConclusionPatients with incurable cancer who received EIPC showed increased use of approach-oriented coping, which was associated with higher QOL and reduced depressive symptoms. Palliative care may improve these outcomes by providing patients with the skills to cope effectively with life-threatening illness.

    更新日期:2017-11-16
  • Anal Cancer Risk Among People With HIV Infection in the United States
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-15
    Vivian Colón-López; Meredith S. Shiels; Mark Machin; Ana P. Ortiz; Howard Strickler; Philip E. Castle; Ruth M. Pfeiffer; Eric A. Engels

    PurposePeople with HIV infection have an elevated risk of anal cancer. However, recent calendar trends are incompletely described, and which population subgroups might benefit from cancer screening is unknown.MethodsWe used linked data from HIV and cancer registries in nine US areas (1996 to 2012). We calculated standardized incidence ratios to compare anal cancer incidence in people with HIV infection with the general population, used Poisson regression to evaluate anal cancer incidence among subgroups of people with HIV and to assess temporal trends, and estimated the cumulative incidence of anal cancer to measure absolute risk.ResultsAmong 447,953 people with HIV infection, anal cancer incidence was much higher than in the general population (standardized incidence ratio, 19.1; 95% CI, 18.1 to 20.0). Anal cancer incidence was highest among men who have sex with men (MSM), increased with age, and was higher in people with AIDS than in those without AIDS (ie, HIV only; adjusted incidence rate ratio, 3.82; 95% CI, 3.27 to 4.46). Incidence among people with HIV increased steeply during 1996 to 2000 (annual percentage change, 32.8%; 95% CI, −1.0% to 78.2%), reached a plateau during 2001 to 2008, and declined during 2008 to 2012 (annual percentage change, −7.2%; 95% CI, −14.4% to 0.6%). Cumulative incidence after a 5-year period was high for MSM with HIV only age 45 to 59 or ≥ 60 years (0.32% to 0.33%) and MSM with AIDS age 30 to 44, 45 to 59, or ≥ 60 years (0.29% to 0.65%).ConclusionAnal cancer incidence is markedly elevated among people with HIV infection, especially in MSM, older individuals, and people with AIDS. Recent declines may reflect delayed benefits of HIV treatment. Groups with high cumulative incidence of anal cancer may benefit from screening.

    更新日期:2017-11-16
  • BRAF V600E Status Alone Is Not Sufficient as a Prognostic Biomarker in Pediatric Low-Grade Glioma
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-15
    David T.W. Jones; Olaf Witt; Stefan M. Pfister

    With multiple targeted small agents entering late-stage clinical trials, we approach a potential turning point in the clinical management of pediatric gliomas, and an accurate and rational basis for the stratification of this patient population is of critical importance. We commend Lassaletta and colleagues1 for their recent article that outlines the molecular-genetic and clinical features of a large, institutional cohort with these tumors, and agree with many of the issues raised; however, we feel that some of the conclusions drawn by Lassaletta et al1 are not fully supported by the data, and that, at times, the clarity and precision that are required for the optimal planning of clinical studies, including patient stratification, are missing. It is clear from this and many other reports that V600E-mutant low-grade gliomas (LGGs) comprise a heterogeneous group of tumors, with divergent histology, location, cooperating genetic alterations, and outcomes. To attempt to group these together under one umbrella designation, in our opinion, is an oversimplification—the presence of V600E alone does not define a distinct entity. The importance of a more precise distinction is highlighted in some of the details of the survival analyses performed Lassaletta and colleagues.

    更新日期:2017-11-16
  • Reply to D.T.W. Jones et al
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-15
    Uri Tabori; Eric Bouffet; Cynthia E. Hawkins

    Pediatric low-grade gliomas (PLGGs) are a heterogeneous group of tumors that require multiple therapeutic interventions and have variable outcomes. As a result of this and the chronic nature of the disease, management of such tumors has long been considered the art of oncology, with different oncologists taking different approaches with no real consensus on the best way to manage these patients. The last decade has transformed the way clinicians approach PLGGs, both with respect to the understanding of the initial molecular alterations that drive tumorigenesis1-3 and the long-term consequences of the disease.4,5 Although, as noted by Jones et al,6 some controversies remain, we have now reached the point at which some treatment approach recommendations can be made. For the treating physician, it is important to decipher the former from the latter.

    更新日期:2017-11-16
  • Randomized, Multicenter, Placebo-Controlled Clinical Trial of Duloxetine Versus Placebo for Aromatase Inhibitor–Associated Arthralgias in Early-Stage Breast Cancer: SWOG S1202
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-14
    N. Lynn Henry; Joseph M. Unger; Anne F. Schott; Louis Fehrenbacher; Patrick J. Flynn; Debra M. Prow; Carl W. Sharer; Gary V. Burton; Charles S. Kuzma; Anna Moseley; Danika L. Lew; Michael J. Fisch; Carol M. Moinpour; Dawn L. Hershman; James L. Wade III

    PurposeAdherence to aromatase inhibitor (AI) therapy for early-stage breast cancer is limited by AI-associated musculoskeletal symptoms (AIMSS). Duloxetine is US Food and Drug Administration approved for treatment of multiple chronic pain disorders. We hypothesized that treatment of AIMSS with duloxetine would improve average joint pain compared with placebo.MethodsThis randomized, double-blind, phase III trial included AI-treated postmenopausal women with early-stage breast cancer and who had average joint pain score of ≥ 4 out of 10 that developed or worsened since AI therapy initiation. Patients were randomly assigned 1:1 to duloxetine or placebo for 13 weeks. The primary end point was average joint pain through 12 weeks, examined using multivariable linear mixed models, adjusted for stratification factors (baseline pain score of 4 to 6 v 7 to 10 and prior taxane use). Clinically significant change in average pain was defined as a ≥ 2-point decrease from baseline.ResultsOf 299 enrolled patients, 127 patients treated with duloxetine and 128 who received placebo were evaluable for the primary analysis. By 12 weeks, the average joint pain score was 0.82 points lower for patients who received duloxetine compared with those who received placebo (95% CI, −1.24 to −0.40; P = .0002). Similar patterns were observed for worst joint pain, joint stiffness, pain interference, and functioning. Rates of adverse events of any grade were higher in the duloxetine-treated group (78% v 50%); rates of grade 3 adverse events were similar.ConclusionResults of treatment with duloxetine for AIMSS were superior to those of placebo among women with early-stage breast cancer, although it resulted in more frequent low-grade toxicities.

    更新日期:2017-11-15
  • Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-13
    David O’Connor; Amir Enshaei; Jack Bartram; Jeremy Hancock; Christine J. Harrison; Rachael Hough; Sujith Samarasinghe; Claire Schwab; Ajay Vora; Rachel Wade; John Moppett; Anthony V. Moorman; Nick Goulden

    PurposeMinimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics.Patients and MethodsWe used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups.ResultsMRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification.ConclusionA single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse.

    更新日期:2017-11-14
  • Integrated Risk Stratification Using Minimal Residual Disease and Sentinel Genetic Alterations in Pediatric Acute Lymphoblastic Leukemia
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-13
    Stephen P. Hunger

    Treatment of pediatric acute lymphoblastic leukemia (ALL) has provided a paradigm for cancer therapy since 1948, when Farber and Diamond1 first demonstrated that chemotherapy could induce remission in human cancer. Once curative therapies for ALL were developed, age and WBC count at diagnosis were identified as important prognostic factors that were predictive of response and outcome.2 It was later found that early response to therapy—as measured by morphologic clearance of blasts from the blood or marrow during induction therapy—was a strong predictor of outcome.3,4 It is now recognized that detection of minimal residual disease (MRD) by either PCR amplification of clonotypic IG/TCR gene rearrangements or flow cytometric detection of leukemia-associated phenotypes is perhaps the strongest predictor of event-free survival (EFS) and overall survival (OS).5-7 The presence of specific recurrent sentinel genetic lesions in leukemia cells is also a powerful prognostic factor.8 There is general agreement, not universal, that good risk factors include ETV6-RUNX1 fusion and high hyperdiploidy and/or favorable chromosome trisomies, whereas poor risk factors include BCR-ABL1 fusion, KMT2A (MLL) gene fusions, intrachromosomal amplification of chromosome 21 (iAMP21), and hypodiploidy.

    更新日期:2017-11-14
  • MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Matthew P. Goetz; Masakazu Toi; Mario Campone; Joohyuk Sohn; Shani Paluch-Shimon; Jens Huober; In Hae Park; Olivier Trédan; Shin-Cheh Chen; Luis Manso; Orit C. Freedman; Georgina Garnica Jaliffe; Tammy Forrester; Martin Frenzel; Susana Barriga; Ian C. Smith; Nawel Bourayou; Angelo Di Leo

    PurposeAbemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy.MethodsMONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events.ResultsMedian progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm (P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%).ConclusionAbemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

    更新日期:2017-11-10
  • Effective Physical Activity Promotion to Survivors of Cancer Is Likely to Be Home Based and to Require Oncologist Participation
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Sarah J. Hardcastle; Paul A. Cohen

    Cancer is a leading cause of disease burden worldwide.1 Public health practitioners and researchers in behavioral medicine recognize the need to find effective physical activity interventions to curb the growth in inactivity and prevent chronic illness in survivors of cancer.2,3 Physical activity prevents cardiovascular disease4,5 and may reduce the risk of cancer recurrence,6-9 yet few survivors meet current physical activity guidelines of 30 minutes per day of moderate-intensity exercise.10 There has been a proliferation of trial interventions, yet only a minority of survivors of cancer receive physical activity advice or referrals to exercise programs as a part of routine care.11-13

    更新日期:2017-11-10
  • Long-Term Use of Long-Acting Insulin Analogs and Breast Cancer Incidence in Women With Type 2 Diabetes
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Jennifer W. Wu; Laurent Azoulay; Agnieszka Majdan; Jean-François Boivin; Michael Pollak; Samy Suissa

    PurposeThe association between long-acting insulin analogs and increased breast cancer risk is uncertain, particularly with the short follow-up in previous studies. We assessed this risk long term in women with type 2 diabetes.MethodsA population-based cohort of women 40 years or older, all of whom were treated with long-acting (glargine, detemir) or neutral protamine Hagedorn (NPH) insulin between 2002 and 2012, was formed using the United Kingdom’s Clinical Practice Research Datalink. Women were followed until February 2015 or breast cancer diagnosis. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% CIs of incident breast cancer, comparing long-acting insulin analogs with NPH overall, as well as by duration and cumulative dose.ResultsThe cohort included 22,395 women who received insulin treatment, with 321 incident breast cancer events occurring during up to 12 years of follow-up (incidence rate 3.3 per 1,000 person-years). Compared with NPH insulin, insulin glargine was associated with an increased risk of breast cancer (HR, 1.44; 95% CI, 1.11 to 1.85), mainly increasing 5 years after glargine initiation (HR, 2.23; 95% CI, 1.32 to 3.77) and after > 30 prescriptions (HR, 2.29; 95% CI, 1.26 to 4.16). The risk was particularly elevated among prior insulin users (HR, 1.53; 95% CI, 1.10 to 2.12) but not for new users, which included fewer patients and for which one cannot rule out an HR of 1.81. The risk associated with insulin detemir was not significantly elevated (HR, 1.17; 95% CI, 0.77 to 1.77).ConclusionLong-term use of insulin glargine is associated with an increased risk of breast cancer in women with type 2 diabetes. The risk associated with insulin detemir remains uncertain because there are fewer users of this insulin.

    更新日期:2017-11-10
  • Associations Between Sexual Orientation and Overall and Site-Specific Diagnosis of Cancer: Evidence From Two National Patient Surveys in England
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Catherine L. Saunders; Catherine Meads; Gary A. Abel; Georgios Lyratzopoulos

    PurposeTo address gaps in evidence on the risk of cancer in people from sexual minorities.Patients and MethodsWe used data from 796,594 population-based English General Practice Patient Survey responders to explore the prevalence of self-reported diagnoses of cancer in the last 5 years among sexual minorities compared with heterosexual women and men. We analyzed data from 249,010 hospital-based English Cancer Patient Experience Survey responders with sexual orientation as a binary outcome, and International Classification of Diseases, Tenth, Revision, diagnosis as covariate—38 different common and rarer cancers, with breast and prostate cancer as baseline categories for women and men, respectively—to examine whether people from sexual minorities are over- or under-represented among different cancer sites. For both analyses, we used logistic regression, stratified by sex and adjusted for age.ResultsA diagnosis of cancer in the past 5 years was more commonly reported by male General Practice Patient Survey responders who endorsed gay or bisexual orientation compared with heterosexual men (odds ratio [OR], 1.31; 95% CI, 1.15 to 1.49; P < .001) without evidence of a difference between lesbian or bisexual compared with heterosexual women (OR, 1.14; 95% CI, 0.94 to 1.37; P = .19). For most common and rarer cancer sites (30 of 33 in women, 28 of 32 in men), the odds of specific cancer site diagnosis among Cancer Patient Experience Survey respondents seemed to be independent of sexual orientation; however, there were notable differences in infection-related (HIV and human papillomavirus [HPV]) cancers. Gay or bisexual men were over-represented among men with Kaposi’s sarcoma (OR, 48.2; 95% CI, 22.0 to 105.6), anal (OR, 15.5; 95% CI, 11.0 to 21.9), and penile cancer (OR, 1.8; 95% CI, 0.9 to 3.7). Lesbian or bisexual women were over-represented among women with oropharyngeal cancer (OR, 3.2; 95% CI, 1.7 to 6.0).ConclusionLarge-scale evidence indicates that the distribution of cancer sites does not vary substantially by sexual orientation, with the exception of some HPV- and HIV-associated cancers. These findings highlight the importance of HPV vaccination in heterosexual and sexual minority populations.

    更新日期:2017-11-10
  • Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Kaoru Kubota; Hiroshige Yoshioka; Fumihiro Oshita; Toyoaki Hida; Kiyotaka Yoh; Hidetoshi Hayashi; Terufumi Kato; Hiroyasu Kaneda; Kazuhiko Yamada; Hiroshi Tanaka; Yukito Ichinose; Keunchil Park; Eun Kyung Cho; Kyung-Hee Lee; Chih-Bin Lin; James Chih-Hsin Yang; Kaori Hara; Takayuki Asato; Kazuhiko Nakagawa

    PurposeThis phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung cancer.Patients and MethodsPatients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m2 IV and carboplatin area under the concentration-time curve 6 mg/mL ⋅ min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs).ResultsFour hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months (P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% (P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade ≥ 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related.ConclusionMotesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung cancer.

    更新日期:2017-11-10
  • Adjuvant Chemoradiotherapy With Epirubicin, Cisplatin, and Fluorouracil Compared With Adjuvant Chemoradiotherapy With Fluorouracil and Leucovorin After Curative Resection of Gastric Cancer: Results From CALGB 80101 (Alliance)
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Charles S. Fuchs; Donna Niedzwiecki; Harvey J. Mamon; Joel E. Tepper; Xing Ye; Richard S. Swanson; Peter C. Enzinger; Daniel G. Haller; Tomislav Dragovich; Steven R. Alberts; Georg A. Bjarnason; Christopher G. Willett; Leonard L. Gunderson; Richard M. Goldberg; Alan P. Venook; David Ilson; Eileen O’Reilly; Kristen Ciombor; David J. Berg; Jeffrey Meyerhardt; Robert J. Mayer

    PurposeAfter curative resection of gastric or gastroesophageal junction adenocarcinoma, Intergroup Trial 0116 (Phase III trial of postoperative adjuvant radiochemotherapy for high risk gastric and gastroesophageal junction adenocarcinoma: Demonstrated superior survival for patients who received postoperative chemoradiotherapy with bolus fluorouracil (FU) and leucovorin (LV) compared with surgery alone. CALGB 80101 (Alliance; Phase III Intergroup Trial of Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma) assessed whether a postoperative chemoradiotherapy regimen that replaced FU plus LV with a potentially more active systemic therapy could further improve overall survival.Patients and MethodsBetween April 2002 and May 2009, 546 patients who had undergone a curative resection of stage IB through IV (M0) gastric or gastroesophageal junction adenocarcinoma were randomly assigned to receive either postoperative FU plus LV before and after combined FU and radiotherapy (FU plus LV arm) or postoperative epirubicin, cisplatin, and infusional FU (ECF) before and after combined FU and radiotherapy (ECF arm).ResultsWith a median follow-up duration of 6.5 years, 5-year overall survival rates were 44% in the FU plus LV arm and 44% in the ECF arm (Plogrank = .69; multivariable hazard ratio, 0.98; 95% CI, 0.78 to 1.24 comparing ECF with FU plus LV). Five-year disease-free survival rates were 39% in the FU plus LV arm and 37% in the ECF arm (Plogrank = .94; multivariable hazard ratio, 0.96; 95% CI, 0.77 to 1.20). In post hoc analyses, the effect of treatment seemed to be similar across all examined patient subgroups.ConclusionAfter a curative resection of gastric or gastroesophageal junction adenocarcinoma, postoperative chemoradiotherapy using a multiagent regimen of ECF before and after radiotherapy does not improve survival compared with standard FU and LV before and after radiotherapy.

    更新日期:2017-11-10
  • Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population-Based Cohort Study
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Lene Sofie Granfeldt Østgård; Mette Nørgaard; Bruno C. Medeiros; Lone Smidstrup Friis; Claudia Schoellkopf; Marianne Tang Severinsen; Claus Werenberg Marcher; Jan Maxwell Nørgaard

    PurposePrevious US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or income and clinical characteristics, treatment, and outcome in AML.MethodsTo investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios [HRs]) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers.ResultsOf 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27).ConclusionIn a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients.

    更新日期:2017-11-10
  • Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Xuexia Wang; Can-Lan Sun; Lindsey Hageman; Kandice Smith; Purnima Singh; Sunil Desai; Douglas S. Hawkins; Melissa M. Hudson; Leo Mascarenhas; Joseph P. Neglia; Kevin C. Oeffinger; A. Kim Ritchey; Leslie L. Robison; Doojduen Villaluna; Wendy Landier; Smita Bhatia

    PurposeSurvivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors.MethodsWe curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls).ResultsWe demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [BRCA2], rs1805389 [LIG4], rs8079544 [TP53], rs25489 [XRCC1], rs1673041 [POLD1], and rs11615 [ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior (P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively.ConclusionIt is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.

    更新日期:2017-11-10
  • Risk of Cardiovascular Ischemic Events After Surgical Castration and Gonadotropin-Releasing Hormone Agonist Therapy for Prostate Cancer: A Nationwide Cohort Study
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Dong-Yi Chen; Lai-Chu See; Jia-Rou Liu; Cheng-Keng Chuang; See-Tong Pang; I-Chang Hsieh; Ming-Shien Wen; Tien-Hsing Chen; Yung-Chang Lin; Chuang-Chi Liaw; Cheng-Lung Hsu; John Wen-Cheng Chang; Chang-Fu Kuo; Wen-Kuan Huang

    PurposeOur aim was to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive androgen-deprivation therapy by surgical castration and those who receive gonadotropin-releasing hormone agonist (GnRHa) therapy.Patients and MethodsBy using the Taiwan National Health Insurance Research Database, we analyzed data from 14,715 patients with PCa diagnosed from January 1, 1997, through December 31, 2011. The patients were treated with bilateral orchiectomy or GnRHa therapy. We used inverse probability of treatment weighting with propensity scores to adjust for the imbalance in covariate baseline values between these two groups. Cox regression models were used to identify risk factors for myocardial infarction (MI), ischemic stroke (IS), and cardiac-related complications.ResultsOverall, 3,578 patients with PCa (24.3%) underwent bilateral orchiectomy and 11,137 patients (75.7%) received GnRHa therapy. Both groups had a similar risk of CV ischemic events (ie, MI or IS; hazard ratio, 1.16; 95% CI, 0.97 to 1.38) during a median follow-up time of 3.3 years. However, during the first 1.5 years of follow-up, there were higher CV ischemic events in the orchiectomy group than in the GnRHa group (hazard ratio, 1.40; 95% CI, 1.04 to 1.88), particularly in patients who were ≥ 65 years of age, had hypertension, had a Charlson comorbidity index score ≥ 3, and had a previous history of MI, IS, or coronary heart disease.ConclusionCompared with bilateral orchiectomy, use of GnRHa does not increase the risk of CV ischemic events in patients with PCa. Nonetheless, orchiectomy is associated with higher rates of CV ischemic events in older patients and those with a history of CV comorbidities within 1.5 years of initiating androgen-deprivation therapy. These findings can help clinicians decide on the optimal castration strategy for individual patients.

    更新日期:2017-11-10
  • Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Thai Huu Ho; Payal Kapur; Jeanette E. Eckel-Passow; Alana Christie; Richard W. Joseph; Daniel J. Serie; John C. Cheville; R. Houston Thompson; Farrah Homayoun; Vandana Panwar; James Brugarolas; Alexander S. Parker

    PurposeEnhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials.MethodsWe performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups.ResultsPatients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001).ConclusionEZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials.

    更新日期:2017-11-10
  • Effect of Inpatient Palliative Care During Hematopoietic Stem-Cell Transplant on Psychological Distress 6 Months After Transplant: Results of a Randomized Clinical Trial
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Areej El-Jawahri; Lara Traeger; Joseph A. Greer; Harry VanDusen; Sarah R. Fishman; Thomas W. LeBlanc; William F. Pirl; Vicki A. Jackson; Jason Telles; Alison Rhodes; Zhigang Li; Thomas R. Spitzer; Steven McAfee; Yi-Bin A. Chen; Jennifer S. Temel

    PurposeInpatient palliative care integrated with transplant care improves patients’ quality of life (QOL) and symptom burden during hematopoietic stem-cell transplant (HCT). We assessed patients’ mood, post-traumatic stress disorder (PTSD) symptoms, and QOL 6 months post-transplant.MethodsWe randomly assigned 160 patients with hematologic malignancies who underwent autologous or allogeneic HCT to inpatient palliative care integrated with transplant care (n = 81) or transplant care alone (n = 79). At baseline and 6 months post-transplant, we assessed mood, PTSD symptoms, and QOL with the Hospital Anxiety and Depression Scale and Patient Health Questionnaire, PTSD checklist, and Functional Assessment of Cancer Therapy-Bone Marrow Transplant. To assess symptom burden during HCT, we used the Edmonton Symptom Assessment Scale. We used analysis of covariance while controlling for baseline values to examine intervention effects and conducted causal mediation analyses to examine whether symptom burden or mood during HCT mediated the effect of the intervention on 6-month outcomes.ResultsWe enrolled 160 (86%) of 186 potentially eligible patients between August 2014 and January 2016. At 6 months post-transplant, intervention participants reported lower depression symptoms on the Hospital Anxiety and Depression Scale and Patient Health Questionnaire (adjusted mean difference, −1.21 [95% CI, −2.26 to −0.16; P = .024] and −1.63 [95% CI, −3.08 to −0.19; P = .027], respectively) and lower PTSD symptoms (adjusted mean difference, −4.02; 95% CI, −7.18 to −0.86; P = .013), but no difference in QOL or anxiety. Symptom burden and anxiety during HCT hospitalization partially mediated the effect of the intervention on depression and PTSD at 6 months post-transplant.ConclusionInpatient palliative care integrated with transplant care leads to improvements in depression and PTSD symptoms at 6 months post-transplant. Reduction in symptom burden and anxiety during HCT partially accounts for the effect of the intervention on these outcomes.

    更新日期:2017-11-10
  • Prognostic Model to Predict Post-Autologous Stem-Cell Transplantation Outcomes in Classical Hodgkin Lymphoma
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Fong Chun Chan; Anja Mottok; Alina S. Gerrie; Maryse Power; Marcel Nijland; Arjan Diepstra; Anke van den Berg; Peter Kamper; Francesco d’Amore; Alexander Lindholm d’Amore; Stephen Hamilton-Dutoit; Kerry J. Savage; Sohrab P. Shah; Joseph M. Connors; Randy D. Gascoyne; David W. Scott; Christian Steidl

    PurposeOur aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT).Materials and MethodsWe performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression–based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation.ResultsGene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry.ConclusionWe have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography–guided response assessment and the evolving cHL treatment landscape.

    更新日期:2017-11-10
  • Brave Journey Home
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10
    Samuel X. Stevens

    We first saw Anita on Tuesday morning. Just 21-years old, her wicked laugh and sarcastic sense of humor had been weathered by weeks of sleeplessness, worry, and pain. Her parents at her bedside, she peered at us with the cautious look of somebody who had little left to hold on to; somebody whose ability to see the beginning of the next day depended on the carefully weighed decisions of the day before. Eleven months earlier, she had her first encounter with juvenile ovarian cancer; 10 kilograms of tumor were resected from her barely adult abdomen. Since then, she had endured a surgical and cytotoxic offense in an attempt to control the rapidly spreading tumor. After undergoing two operations and two rounds of chemotherapy, her last hopes of surviving her terrible disease were pinned on a trial treatment, scheduled to start the next week.

    更新日期:2017-11-10
  • Safety and Antitumor Activity of the Anti–Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-08
    Toshihiko Doi; Sarina A. Piha-Paul; Shadia I. Jalal; Sanatan Saraf; Jared Lunceford; Minori Koshiji; Jaafar Bennouna

    PurposeThe anti–programmed death-1 antibody pembrolizumab was evaluated in KEYNOTE-028, a multicohort, phase IB study of patients with programmed death ligand-1 (PD-L1)–positive advanced solid tumors. Results from the esophageal carcinoma cohort are reported herein.Patients and MethodsEligible patients with squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction in whom standard therapy failed and who had PD-L1–positive tumors received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or intolerable toxicity. Response was assessed every 8 weeks up to 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate, determined by investigator review per Response Evaluation Criteria in Solid Tumors (version 1.1).ResultsAmong 83 patients with esophageal carcinoma and samples evaluable for PD-L1 expression, 37 (45%) had PD-L1–positive tumors, and 23 were enrolled. Median age was 65 years; 78% had squamous histology; and 87% received ≥ two prior therapies for advanced/metastatic disease. As of the data cutoff (February 20, 2017), median follow-up was 7 months (range, 1 to 33 months). Nine patients (39%) experienced treatment-related adverse events, most commonly decreased appetite, decreased lymphocyte count, generalized rash, and rash (two patients [9%] each). No grade 4 adverse events or deaths were attributed to pembrolizumab. Overall response rate was 30% (95% CI, 13% to 53%); median duration of response was 15 months (range, 6 to 26 months). A six-gene interferon-γ gene expression signature analysis suggested that delayed progression and increased response occur among pembrolizumab-treated patients with higher interferon-γ composite scores.ConclusionPembrolizumab demonstrated manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1–positive advanced esophageal carcinoma.

    更新日期:2017-11-09
  • Alcohol and Cancer: A Statement of the American Society of Clinical Oncology
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-07
    Noelle K. LoConte; Abenaa M. Brewster; Judith S. Kaur; Janette K. Merrill; Anthony J. Alberg

    Alcohol drinking is an established risk factor for several malignancies, and it is a potentially modifiable risk factor for cancer. The Cancer Prevention Committee of the American Society of Clinical Oncology (ASCO) believes that a proactive stance by the Society to minimize excessive exposure to alcohol has important implications for cancer prevention. In addition, the role of alcohol drinking on outcomes in patients with cancer is in its formative stages, and ASCO can play a key role by generating a research agenda. Also, ASCO could provide needed leadership in the cancer community on this issue. In the issuance of this statement, ASCO joins a growing number of international organizations by establishing a platform to support effective public health strategies in this area. The goals of this statement are to: • Promote public education about the risks between alcohol abuse and certain types of cancer; • Support policy efforts to reduce the risk of cancer through evidence-based strategies that prevent excessive use of alcohol; • Provide education to oncology providers about the influence of excessive alcohol use and cancer risks and treatment complications, including clarification of conflicting evidence; and • Identify areas of needed research regarding the relationship between alcohol use and cancer risk and outcomes.

    更新日期:2017-11-08
  • Errata
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10

    The February 20, 2017, article by Choueiri, et al, entitled “Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial” (J Clin Oncol 35:591-597), was published with errors. The investigator team upon detailed review of the study charts found errors or significant changes from the original report.

    更新日期:2017-11-08
  • Errata
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-10

    The April 10, 2017, article by van den Bogaard et al, entitled “Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures” (J Clin Oncol 35:1171-1178), was published with errors.

    更新日期:2017-11-08
  • Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-06
    Bryan J. Schneider; Megan E. Daly; Erin B. Kennedy; Mara B. Antonoff; Stephen Broderick; Jill Feldman; Shruti Jolly; Bryan Meyers; Gaetano Rocco; Chad Rusthoven; Ben J. Slotman; Daniel H. Sterman; Brendon M. Stiles

    PurposeThe American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on treatment with stereotactic body radiotherapy (SBRT) for patients with early-stage non–small-cell lung cancer. ASCO has a policy and set of procedures for endorsing and/or adapting clinical practice guidelines that have been developed by other professional organizations.MethodsThe ASTRO Evidence-Based Guideline for Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer was reviewed for developmental rigor by methodologists. An ASCO Expert Panel updated the literature search and reviewed the guideline content and recommendations.ResultsThe ASCO Expert Panel determined that the recommendations from the ASTRO guideline, published in 2017, are clear, thorough, and based on the most relevant scientific evidence. ASCO statements and minor modifications were added to enhance the applicability of the ASTRO guideline for the broader ASCO audience.RecommendationsFor standard operative risk patients with stage I NSCLC, SBRT is not recommended outside of a clinical trial. Lobectomy with systematic lymph node evaluation remains the recommended treatment, although a sublobar resection may be considered in select clinical scenarios. Recommendations are provided regarding the use of SBRT in high operative risk patients and for inoperative patients, including in challenging scenarios where tumors are: centrally located, > 5 cm in diameter, lacking tissue diagnosis, synchronous primary or multifocal, second primary after pneumonectomy, proximal to or involved with mediastinal structures, abutting the chest wall, or recurring after previous treatment. Qualifying statements are included to provide further guidance for implementation, and the importance of a discussion of treatment options among members of the multidisciplinary cancer care team is emphasized. Additional information is available at: www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki.

    更新日期:2017-11-07
  • Chemoimmunotherapy May Not Be Dead Yet in Chronic Lymphocytic Leukemia, But Fludarabine Plus Cyclophosphamide Plus Rituximab Is Potentially Facing Life Support
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-03
    Stephen Opat; Eliza A. Hawkes

    In their recent commentary in Journal of Clinical Oncology, Brown and Kay1 state that “chemoimmunotherapy is not dead yet in chronic lymphocytic leukemia” and extol the virtues of fludarabine plus cyclophosphamide plus rituximab (FCR). We agree with the generally cautious approach to early adoption of novel agents in chronic lymphocytic leukemia (CLL) and the ongoing central role of chemoimmunotherapy. However, although FCR yields good long-term results in a proportion of patients, this cohort is small. We are concerned that there remains a lack of emphasis in the literature on the poor suitability of most patients with CLL for FCR. In our opinion, FCR is associated with unacceptable levels of both early and late toxicity, particularly in older patients, with morbidity evident in clinical practice that is poorly reflected in clinical trials.

    更新日期:2017-11-05
  • Reply to S. Opat et al
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-03
    Jennifer R. Brown; Neil E. Kay

    We thank Opat and Hawkes1 for their letter to the editor in response to our recent article in Journal of Clinical Oncology titled “Chemoimmunotherapy Is Not Dead Yet in Chronic Lymphocytic Leukemia.”2 In particular, we appreciate that they agree with the ongoing role of chemoimmunotherapy (CIT) in the treatment of chronic lymphocytic leukemia (CLL) and with our cautious approach to major shifts in therapy on the basis of limited short-term data. Their primary concerns focus on the role of fludarabine plus cyclophosphamide plus rituximab (FCR) and its toxicity, although they acknowledge the superiority of FCR among fit patients with CLL with mutated immunoglobulin heavy-chain variable-region. Indeed, one of our goals was to remind the community that the long-term efficacy data with FCR demonstrate a plateau on the progression-free survival (PFS) curve at > 12 years in patients with mutated immunoglobulin heavy-chain variable-region, with those who were tested negative for minimal residual disease, raising the possibility of cure. These data establish the superiority of FCR to other CIT regimens, none of which show a PFS plateau, and indicate that, as stated in our commentary, FCR is the regimen of choice when appropriate. Opat and Hawkes raise extremely valid concerns about acute toxicity when FCR is inappropriately used in unfit older patients. However, their concerns about appropriate patient selection and management apply to all therapies, including ibrutinib, which has proven more toxic in community use than expected from clinical trials,3,4 the so-called real world effect. Indeed, with FCR, the clear eligibility criteria of the German CLL Study Group trials provide unusually specific and sound guidance in defining which patients are sufficiently fit for FCR.5 Furthermore, most published studies on FCR have unfortunately not mandated the use of supportive care, which we commonly use and which mitigates toxicity, including anti-infective prophylaxis and prophylactic myeloid growth factors. Their argument that FCR dose reductions are associated with reduced PFS is not relevant, because these patients do not fare more poorly than patients receiving less effective CIT regimens. In fact, the median PFS for patients with FCR dose reduction in the study by Kovacs et al6 cited by Opat and Hawkes is still better than the median PFS for those treated with upfront bendamustine and rituximab.5

    更新日期:2017-11-05
  • Randomized Trial of ConquerFear: A Novel, Theoretically Based Psychosocial Intervention for Fear of Cancer Recurrence
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-02
    Phyllis N. Butow; Jane Turner; Jemma Gilchrist; Louise Sharpe; Allan Ben Smith; Joanna E. Fardell; Stephanie Tesson; Rachel O’Connell; Afaf Girgis; Val J. Gebski; Rebecca Asher; Cathrine Mihalopoulos; Melanie L. Bell; Karina Grunewald Zola; Jane Beith; Belinda Thewes

    Purpose Fear of cancer recurrence (FCR) is prevalent, distressing, and long lasting. This study evaluated the impact of a theoretically/empirically based intervention (ConquerFear) on FCR. Methods Eligible survivors had curable breast or colorectal cancer or melanoma, had completed treatment (not including endocrine therapy) 2 months to 5 years previously, were age > 18 years, and had scores above the clinical cutoff on the FCR Inventory (FCRI) severity subscale at screening. Participants were randomly assigned at a one-to-one ratio to either five face-to-face sessions of ConquerFear (attention training, metacognitions, acceptance/mindfulness, screening behavior, and values-based goal setting) or an attention control (Taking-it-Easy relaxation therapy). Participants completed questionnaires at baseline (T0), immediately post-therapy (T1), and 3 (T2) and 6 months (T3) later. The primary outcome was FCRI total score. Results Of 704 potentially eligible survivors from 17 sites and two online databases, 533 were contactable, of whom 222 (42%) consented; 121 were randomly assigned to intervention and 101 to control. Study arms were equivalent at baseline on all measured characteristics. ConquerFear participants had clinically and statistically greater improvements than control participants from T0 to T1 on FCRI total (P < .001) and severity subscale scores (P = .001), which were maintained at T2 (P = .017 and P = .023, respectively) and, for FCRI total only, at T3 (P = .018), and from T0 to T1 on three FCRI subscales (coping, psychological distress, and triggers) as well as in general anxiety, cancer-specific distress (total), and mental quality of life and metacognitions (total). Differences in FCRI psychological distress and cancer-specific distress (total) remained significantly different at T3. Conclusion This randomized trial demonstrated efficacy of ConquerFear compared with attention control (Taking-it-Easy) in reduction of FCRI total scores immediately post-therapy and 3 and 6 months later and in many secondary outcomes immediately post-therapy. Cancer-specific distress (total) remained more improved at 3- and 6-month follow-up.

    更新日期:2017-11-03
  • Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-02
    Stefano Luminari; Angela Ferrari; Martina Manni; Alessandra Dondi; Annalisa Chiarenza; Francesco Merli; Chiara Rusconi; Vittoria Tarantino; Alessandra Tucci; Umberto Vitolo; Sofia Kovalchuk; Emanuele Angelucci; Alessandro Pulsoni; Luca Arcaini; Francesco Angrilli; Gianluca Gaidano; Caterina Stelitano; Giovanni Bertoldero; Nicola Cascavilla; Flavia Salvi; Andrés J.M. Ferreri; Daniele Vallisa; Luigi Marcheselli; Massimo Federico

    Purpose The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years. Patients and Methods Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months). Results The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP. Conclusion With an 83% 8-year OS rate, long-term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy.

    更新日期:2017-11-03
  • Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1–Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-02
    Jean-Sebastien Frenel; Christophe Le Tourneau; Bert O’Neil; Patrick A. Ott; Sarina A. Piha-Paul; Carlos Gomez-Roca; Emilie M.J. van Brummelen; Hope S. Rugo; Shari Thomas; Sanatan Saraf; Reshma Rangwala; Andrea Varga

    Purpose The KEYNOTE-028 trial (ClinicalTrials.gov identifier: NCT02054806) was designed to assess the safety and efficacy of pembrolizumab in 20 programmed death ligand 1–positive, advanced solid tumor cohorts. Here, we present the results from the cohort of patients with advanced cervical cancer. Methods Patients were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was overall response rate per Response Evaluation Criteria in Solid Tumors, version 1.1, by investigator review. Safety was a secondary end point. Results Twenty-four patients were enrolled in the cervical cancer cohort. The median age was 42 years (range, 26 to 62 years), 22 patients (92%) had received prior radiation therapy, and 15 patients (63%) had received two or more lines of therapy, including bevacizumab (10 of 24 patients), for advanced disease. At the data cutoff, median follow-up duration was 11.0 months (range, 1.3 to 32.2 months). Overall response rate was 17% (95% CI, 5% to 37%); four patients (17%) achieved a confirmed partial response, and three patients (13%) had stable disease. Median duration of response for the four patients who achieved a partial response was 5.4 months (4.1 to 7.5 months). Treatment related adverse events (AEs) were experienced by 18 patients (75%); only rash (n = 5; 21%) and pyrexia (n = 4; 17%) and occurred in ≥ 10% of patients. Five patients experienced grade 3 treatment-related AEs. No grade 4 treatment-related AEs or deaths were observed. Conclusion In patients with programmed death ligand 1–positive advanced cervical cancer, pembrolizumab demonstrated antitumor activity and exhibited a safety profile consistent with that seen in other tumor types.

    更新日期:2017-11-03
  • Prediction of Ischemic Heart Disease and Stroke in Survivors of Childhood Cancer
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-02
    Eric J. Chow; Yan Chen; Melissa M. Hudson; Elizabeth A.M. Feijen; Leontien C. Kremer; William L. Border; Daniel M. Green; Lillian R. Meacham; Daniel A. Mulrooney; Kirsten K. Ness; Kevin C. Oeffinger; Cécile M. Ronckers; Charles A. Sklar; Marilyn Stovall; Helena J. van der Pal; Irma W.E.M. van Dijk; Flora E. van Leeuwen; Rita E. Weathers; Leslie L. Robison; Gregory T. Armstrong; Yutaka Yasui

    Purpose We aimed to predict individual risk of ischemic heart disease and stroke in 5-year survivors of childhood cancer. Patients and Methods Participants in the Childhood Cancer Survivor Study (CCSS; n = 13,060) were observed through age 50 years for the development of ischemic heart disease and stroke. Siblings (n = 4,023) established the baseline population risk. Piecewise exponential models with backward selection estimated the relationships between potential predictors and each outcome. The St Jude Lifetime Cohort Study (n = 1,842) and the Emma Children’s Hospital cohort (n = 1,362) were used to validate the CCSS models. Results Ischemic heart disease and stroke occurred in 265 and 295 CCSS participants, respectively. Risk scores based on a standard prediction model that included sex, chemotherapy, and radiotherapy (cranial, neck, and chest) exposures achieved an area under the curve and concordance statistic of 0.70 and 0.70 for ischemic heart disease and 0.63 and 0.66 for stroke, respectively. Validation cohort area under the curve and concordance statistics ranged from 0.66 to 0.67 for ischemic heart disease and 0.68 to 0.72 for stroke. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were < 5%, compared with approximately 20% for high-risk groups (P < .001); cumulative incidence was only 1% for siblings (P < .001 v low-risk survivors). Conclusion Information available to clinicians soon after completion of childhood cancer therapy can predict individual risk for subsequent ischemic heart disease and stroke with reasonable accuracy and discrimination through age 50 years. These models provide a framework on which to base future screening strategies and interventions.

    更新日期:2017-11-03
  • Improving Breast Cancer Screening and Care for Women With Severe Mental Illness
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-02
    Alison R. Hwong; Christina Mangurian

    The evidence is clear that people with severe mental illness, such as schizophrenia and bipolar disorder, die earlier than the general US population.1-3 Their lives are shortened by an estimated 10 to 30 years, and that mortality risk appears to be increasing.4 The leading causes of death are cardiovascular disease and cancer,5 which suggests that a better understanding of ways to provide preventive services to the population with severe mental illness could help to reduce the number of these premature deaths.

    更新日期:2017-11-03
  • Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-11-01
    Jorge E. Cortes; Carlo Gambacorti-Passerini; Michael W. Deininger; Michael J. Mauro; Charles Chuah; Dong-Wook Kim; Irina Dyagil; Nataliia Glushko; Dragana Milojkovic; Philipp le Coutre; Valentin Garcia-Gutierrez; Laurence Reilly; Allison Jeynes-Ellis; Eric Leip; Nathalie Bardy-Bouxin; Andreas Hochhaus; Tim H. Brümmendorf

    PurposeBosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome–positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of bosutinib versus imatinib for first-line treatment of chronic-phase CML.MethodsIn this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of bosutinib once daily (n = 268) or imatinib (n = 268). Per protocol, efficacy was assessed in patients who were Philadelphia chromosome–positive with typical (e13a2/e14a2) transcripts (bosutinib, n = 246; imatinib, n = 241). Patients with Philadelphia chromosome–negative–/BCR-ABL1–positive status and those with unknown Philadelphia chromosome status and/or atypical BCR-ABL1 transcript type were excluded from this population.ResultsThe major molecular response (MMR) rate at 12 months (primary end point) was significantly higher with bosutinib versus imatinib (47.2% v 36.9%, respectively; P = .02), as was complete cytogenetic response (CCyR) rate by 12 months (77.2% v 66.4%, respectively; P = .0075). Cumulative incidence was favorable with bosutinib (MMR: hazard ratio, 1.34; P = .0173; CCyR: hazard ratio, 1.38; P < .001), with earlier response times. Four patients (1.6%) receiving bosutinib and six patients (2.5%) receiving imatinib experienced disease progression to accelerated/blast phase. Among treated patients, 22.0% of patients receiving bosutinib and 26.8% of patients receiving imatinib discontinued treatment, most commonly for drug-related toxicity (12.7% and 8.7%, respectively). Grade ≥ 3 diarrhea (7.8% v 0.8%) and increased ALT (19.0% v 1.5%) and AST (9.7% v 1.9%) levels were more common with bosutinib. Cardiac and vascular toxicities were uncommon.ConclusionPatients who received bosutinib had significantly higher rates of MMR and CCyR and achieved responses faster than those who received imatinib. Consistent with the known safety profile, GI events and transaminase elevations were more common with bosutinib. Results indicate bosutinib may be an effective first-line treatment for chronic-phase CML.

    更新日期:2017-11-02
  • Advancing the Science of Cancer Health Disparities Research
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-31
    Lauren P. Wallner; Jennifer J. Griggs

    It is not news that significant disparities in cancer-related outcomes exist across race and ethnicity. There is a wealth of literature to document disparate care, particularly with respect to black versus white disparities in cancer survival.1,2 Disparities in cancer-specific survival go beyond just race/ethnicity, however, and include differences across sociodemographic characteristics, including individual socioeconomic position (education, income),2 insurance status,3 neighborhood socioeconomic status (SES),4,5 and marital status.6 In addition, it is well established that differences in clinical factors contribute to the disparities seen in survival after cancer, including varying tumor characteristics at diagnosis, differences in treatment, access to health care, and health-seeking behaviors.7

    更新日期:2017-11-01
  • Antithymocyte Globulin for Graft-Versus-Host Disease Prophylaxis After Allogeneic Hematopoietic Stem-Cell Transplantation
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-31
    Mohamad Mohty; Florent Malard

    Chronic graft-versus-host disease (GVHD) is a systemic syndrome that presents with variable, often extensive, clinical features, which mimic autoimmune disease and other immunologic disorders, such as systemic sclerosis, lupus erythematosus, or Sjögren syndrome.1 Chronic GVHD remains an important limiting factor for the success of allogeneic hematopoietic stem-cell transplantation (allo-HSCT), mostly because of associated complications, namely infections and organ failure. Thus, chronic GVHD is the leading cause of late nonrelapse mortality (NRM) and morbidity after allo-HSCT. Allo-HSCT using granulocyte colony-stimulating factor–mobilized peripheral blood stem cells (PBSC) from HLA-matched unrelated or HLA-mismatched donors, which are well-identified risk factors for chronic GVHD,2,3 is on the rise.4 Data from the Center for International Blood and Marrow Transplant Research showed increased incidence of chronic GVHD5 in these types of transplant.

    更新日期:2017-11-01
  • Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-26
    Vivek Subbiah; Robert J. Kreitman; Zev A. Wainberg; Jae Yong Cho; Jan H.M. Schellens; Jean Charles Soria; Patrick Y. Wen; Christoph Zielinski; Maria E. Cabanillas; Gladys Urbanowitz; Bijoyesh Mookerjee; Dazhe Wang; Fatima Rangwala; Bhumsuk Keam

    Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E–mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E–mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E–mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

    更新日期:2017-10-27
  • International Assessment of Event-Free Survival at 24 Months and Subsequent Survival in Peripheral T-Cell Lymphoma
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-26
    Matthew J. Maurer; Fredrik Ellin; Line Srour; Mats Jerkeman; N. Nora Bennani; Joseph M. Connors; Graham W. Slack; Karin E. Smedby; Stephen M. Ansell; Brian K. Link; James R. Cerhan; Thomas Relander; Kerry J. Savage; Andrew L. Feldman

    Purpose Peripheral T-cell lymphomas (PTCLs) have aggressive clinical behavior. We have previously shown that event-free survival (EFS) at 24 months (EFS24) is a clinically useful end point in diffuse large B-cell lymphoma. Here, we assess EFS24 and subsequent overall survival (OS) in large, multinational PTCL cohorts. Patients and Methods Patients with systemic PTCL newly diagnosed from 2000 to 2012 and treated with curative intent were included from the United States and Sweden (initial cohorts) and from Canada (replication cohort). EFS was defined as time from date of diagnosis to progression after primary treatment, retreatment, or death. Subsequent OS was measured after achieving EFS24 or from the time of progression if it occurred within 24 months. OS rates were compared with the age-, sex-, and country-matched general population. Results Seven hundred seventy-five patients were included in the study (the median age at diagnosis was 64 years; 63% were men). Results were similar in the initial and replication cohorts, and a combined analysis was undertaken. Sixty-four percent of patients progressed within the first 24 months and had a median OS of only 4.9 months (5-year OS, 11%). In contrast, median OS after achieving EFS24 was not reached (5-year OS, 78%), although relapses within 5 years of achieving EFS24 occurred in 23% of patients. Superior outcomes after achieving EFS24 were observed in younger patients (≤ 60 years of age: 5-year OS, 91%). Conclusion EFS24 stratifies subsequent outcome in PTCL. Patients with PTCL with primary refractory disease or early relapse have extremely poor survival. However, more than one third of patients with PTCL remain in remission 2 years after diagnosis with encouraging subsequent OS, especially in younger patients. These marked differences in outcome suggest that EFS24 has utility for patient counseling, study design, and risk stratification in PTCL.

    更新日期:2017-10-27
  • Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-26
    Patricia A. Ganz; Edward H. Romond; Reena S. Cecchini; Priya Rastogi; Charles E. Geyer Jr; Sandra M. Swain; Jong-Hyeon Jeong; Louis Fehrenbacher; Howard M. Gross; Adam M. Brufsky; Patrick J. Flynn; Tanya A. Wahl; Thomas E. Seay; James L. Wade III; David D. Biggs; James N. Atkins; Jonathan Polikoff; John L. Zapas; Eleftherios P. Mamounas; Norman Wolmark

    Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2–positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.

    更新日期:2017-10-27
  • Maintenance Poly (ADP-ribose) Polymerase Inhibitor Therapy for Ovarian Cancer: Precision Oncology or One Size Fits All?
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-26
    Andrew Berchuck; Angeles Alvarez Secord; Haley A. Moss; Laura J. Havrilesky

    Platinum/taxane combinations are the most effective regimens for treatment of epithelial ovarian cancer. Response varies between patients, but because the molecular basis for resistance is not defined, patients receive so-called one size fits all therapy. In contrast, elucidation of the molecular events that cause cancer and regulate its progression has led to the development of precision therapies for cancer. One early example is trastuzumab, an anti–human epidermal growth factor receptor 2/neu antibody used to treat breast cancers that overexpress this receptor tyrosine kinase. Immunohistochemical and fluorescence in situ hybridization tests for human epidermal growth factor receptor 2/neu guide its use. Patients lacking overexpression are spared the toxicity and cost of an expensive drug that is unlikely to provide benefit. In the wake of early successes in precision oncology, the US Food and Drug Administration (FDA) promulgated a model in which companion diagnostic (CDx) tests would be developed and approved in parallel with targeted therapies.

    更新日期:2017-10-27
  • Predictors of Posthospital Transitions of Care in Patients With Advanced Cancer
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-25
    Daniel E. Lage; Ryan D. Nipp; Sara M. D'Arpino; Samantha M. Moran; P. Connor Johnson; Risa L. Wong; William F. Pirl; Ephraim P. Hochberg; Lara N. Traeger; Vicki A. Jackson; Barbara J. Cashavelly; Holly S. Martinson; Joseph A. Greer; David P. Ryan; Jennifer S. Temel; Areej El-Jawahri

    Purpose Patients with advanced cancer experience potentially burdensome transitions of care after hospitalizations. We examined predictors of discharge location and assessed the relationship between discharge location and survival in this population. Methods We conducted a prospective study of 932 patients with advanced cancer who experienced an unplanned hospitalization between September 2014 and March 2016. Upon admission, we assessed patients’ physical symptoms (Edmonton Symptom Assessment System) and psychological distress (Patient Health Questionnaire-4). The primary outcome was discharge location (home without hospice, postacute care [PAC], or hospice [any setting]). The secondary outcome was survival. Results Of 932 patients, 726 (77.9%) were discharged home without hospice, 118 (12.7%) were discharged to PAC, and 88 (9.4%) to hospice. Those discharged to PAC and hospice reported high rates of severe symptoms, including dyspnea, constipation, low appetite, fatigue, depression, and anxiety. Using logistic regression, patients discharged to PAC or hospice versus home without hospice were more likely to be older (odds ratio [OR], 1.03; 95% CI, 1.02 to 1.05; P < .001), live alone (OR, 1.95; 95% CI, 1.25 to 3.02; P < .003), have impaired mobility (OR, 5.08; 95% CI, 3.46 to 7.45; P < .001), longer hospital stays (OR, 1.15; 95% CI, 1.11 to 1.20; P < .001), higher Edmonton Symptom Assessment System physical symptoms (OR, 1.02; 95% CI, 1.003 to 1.032; P < .017), and higher Patient Health Questionnaire-4 depression symptoms (OR, 1.13; 95% CI, 1.01 to 1.25; P < .027). Patients discharged to hospice rather than PAC were more likely to receive palliative care consultation (OR, 4.44; 95% CI, 2.12 to 9.29; P < .001) and have shorter hospital stays (OR, 0.84; 95% CI, 0.77 to 0.91; P < .001). Patients discharged to PAC versus home had lower survival (hazard ratio, 1.53; 95% CI, 1.22 to 1.93; P < .001). Conclusion Patients with advanced cancer who were discharged to PAC facilities and hospice had substantial physical and psychological symptom burden, impaired physical function, and inferior survival compared with those discharged to home. These patients may benefit from interventions to enhance their quality of life and care.

    更新日期:2017-10-26
  • MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-25
    Emilia L. Lim; Diane L. Trinh; Rhonda E. Ries; Jim Wang; Robert B. Gerbing; Yussanne Ma; James Topham; Maya Hughes; Erin Pleasance; Andrew J. Mungall; Richard Moore; Yongjun Zhao; Richard Aplenc; Lillian Sung; E. Anders Kolb; Alan Gamis; Malcolm Smith; Daniela S. Gerhard; Todd A. Alonzo; Soheil Meshinchi; Marco A. Marra

    Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

    更新日期:2017-10-26
  • Adjuvant Pazopanib Does Not PROTECT Against Recurrence of High-Risk, Initially Localized Renal Cell Cancer but Does Provide Novel Insights
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-25
    Grant D. Stewart; Bradley C. Leibovich; Sylvie Negrier; Robert A. Figlin

    Improved postsurgical management to prevent subsequent progression among the 70% of patients with renal cell cancer (RCC) who present to urologic surgeons with initially localized RCC is an area of great need in urologic oncology. When considering all comers, 50% of patients with initially localized RCC will develop recurrent disease in the 10 years after nephrectomy.1 This rate of recurrence rises to > 75% for patients deemed at high risk for recurrence,2 at which point the disease is rarely curable. Postsurgery, patients with RCC are often surprised to hear that, unlike in other cancers, there is no evidence that adjuvant therapy improves survival. As such, the urologic oncology clinical and patient communities have been closely following the rapidly emerging evidence around use of targeted therapy as an adjuvant strategy for initially localized RCC. The assumption that agents that have proven successful in treating metastatic RCC will also be efficacious in micrometastatic RCC led to the development of a series of RCC adjuvant tyrosine kinase inhibitor (TKI) trials, recruitment for which started in 2007.3 The results of the PROTECT (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy) trial,4 published in the article that accompanies this editorial, represent the third report of a double-blind, placebo-controlled, randomized phase III trial of adjuvant vascular endothelial growth factor receptor (VEGFR) TKIs. PROTECT is reported at a fascinating juncture with our existing evidence base consisting of one large negative study of adjuvant sunitinib or sorafinib (ASSURE [Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma])5 and one smaller positive study of adjuvant sunitinib (S-TRAC [Sunitinib as Adjuvant Treatment for Patients at High Risk of Recurrence of Renal Cell Carcinoma Following Nephrectomy]) demonstrating a hazard ratio (HR) of 0.76 (P = .03), providing a 1.2-year delay in disease-free survival (DFS) versus placebo.6

    更新日期:2017-10-26
  • Radiation Therapy for Oropharyngeal Squamous Cell Carcinoma: American Society of Clinical Oncology Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-24
    Harry Quon; Neha Vapiwala; Arlene Forastiere; Erin B. Kennedy; David J. Adelstein; Holly Boykin; Joseph A. Califano; F. Chris Holsinger; Brian Nussenbaum; David I. Rosenthal; Lillian L. Siu; John N. Waldron

    Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy in oropharyngeal squamous cell carcinoma (OPSCC) that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership. After applying standard critical appraisal policy and endorsement procedures, ASCO chose to endorse the ASTRO guideline. Methods The ASTRO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO Expert Panel was convened to review the guideline contents and recommendations. The ASCO guideline approval body, the Clinical Practice Guidelines Committee, approved the final endorsement. Results The ASCO Expert Panel determined that the ASTRO guideline recommendations, published in July 2017, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the ASTRO guideline and added minor qualifying statements. Recommendations Recommendations for the addition of systemic therapy to definitive radiotherapy in the treatment of OPSCC, postoperative radiotherapy with and without systemic therapy following primary surgery of OPSCC, induction chemotherapy in the treatment of OPSCC, and the appropriate dose, fractionation, and volume regimens with and without systemic therapy in the treatment of OPSCC are outlined for a variety of disease stages and clinical scenarios. ASCO Endorsement Panel qualifying statements and minor modifications were made to the ASTRO recommendations. The staging system that is referenced in these guidelines is the American Joint Committee on Cancer Staging Manual, 7th edition. Additional information is available at: www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki.

    更新日期:2017-10-25
  • Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children’s Oncology Group Study
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-23
    Emilia Modolo Pinto; Carlos Rodriguez-Galindo; Stanley B. Pounds; Lei Wang; Michael R. Clay; Geoffrey Neale; Elizabeth A.R. Garfinkle; Catherine G. Lam; Carolyn Fein Levy; Alberto S. Pappo; Gerard P. Zambetti; Raul C. Ribeiro

    Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

    更新日期:2017-10-24
  • Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non–Small-Cell Lung Cancer
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-20
    Reinhard Büttner; John R. Gosney; Birgit Guldhammer Skov; Julien Adam; Noriko Motoi; Kenneth J. Bloom; Manfred Dietel; John W. Longshore; Fernando López-Ríos; Frédérique Penault-Llorca; Giuseppe Viale; Andrew C. Wotherspoon; Keith M. Kerr; Ming-Sound Tsao

    Purpose Three programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of non–small-cell lung cancer (NSCLC). Treatment with pembrolizumab in NSCLC requires PD-L1 immunohistochemistry (IHC) testing. Nivolumab and atezolizumab are approved without PD-L1 testing, though US Food and Drug Administration-cleared complementary PD-L1 tests are available for both. PD-L1 IHC assays used to assess PD-L1 expression in patients treated with programmed death-1/PD-L1 inhibitors in clinical trials include PD-L1 IHC 28-8 pharmDx (28-8), PD-L1 IHC 22C3 pharmDx (22C3), Ventana PD-L1 SP142 (SP142), and Ventana PD-L1 SP263 (SP263). Differences in antibodies and IHC platforms have raised questions about comparability among these assays and their diagnostic use. This review provides practical information to help physicians and pathologists understand analytical features and comparability of various PD-L1 IHC assays and their diagnostic use. Methods We reviewed and summarized published or otherwise reported studies (January 2016 to January 2017) on clinical trial and laboratory-developed PD-L1 IHC assays (LDAs). Studies assessing the effect of diagnostic methods on PD-L1 expression levels were analyzed to address practical issues related to tissue samples used for testing. Results High concordance and interobserver reproducibility were observed with the 28-8, 22C3, and SP263 clinical trial assays for PD-L1 expression on tumor cell membranes, whereas lower PD-L1 expression was detected with SP142. Immune-cell PD-L1 expression was variable and interobserver concordance was poor. Inter- and intratumoral heterogeneity had variable effects on PD-L1 expression. Concordance among LDAs was variable. Conclusion High concordance among 28-8, 22C3, and SP263 when assessing PD-L1 expression on tumor cell membranes suggests possible interchangeability of their clinical use for NSCLC but not for assessment of PD-L1 expression on immune cells. Development of LDAs requires stringent standardization before their recommendation for routine clinical use.

    更新日期:2017-10-21
  • New Persistent Opioid Use Among Patients With Cancer After Curative-Intent Surgery
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-19
    Jay Soong-Jin Lee; Hsou Mei Hu; Anthony L. Edelman; Chad M. Brummett; Michael J. Englesbe; Jennifer F. Waljee; Jeffrey B. Smerage; Jennifer J. Griggs; Hari Nathan; Jacqueline S. Jeruss; Lesly A. Dossett

    PurposeThe current epidemic of prescription opioid misuse has increased scrutiny of postoperative opioid prescribing. Some 6% to 8% of opioid-naïve patients undergoing noncancer procedures develop new persistent opioid use; however, it is unknown if a similar risk applies to patients with cancer. We sought to define the risk of new persistent opioid use after curative-intent surgery, identify risk factors, and describe changes in daily opioid dose over time after surgery.MethodsUsing a national data set of insurance claims, we identified patients with cancer undergoing curative-intent surgery from 2010 to 2014. We included melanoma, breast, colorectal, lung, esophageal, and hepato-pancreato-biliary/gastric cancer. Primary outcomes were new persistent opioid use (opioid-naïve patients who continued filling opioid prescriptions 90 to 180 days after surgery) and daily opioid dose (evaluated monthly during the year after surgery). Logistic regression was used to identify risk factors for new persistent opioid use.ResultsA total of 68,463 eligible patients underwent curative-intent surgery and filled opioid prescriptions. Among opioid-naïve patients, the risk of new persistent opioid use was 10.4% (95% CI, 10.1% to 10.7%). One year after surgery, these patients continued filling prescriptions with daily doses similar to chronic opioid users (P = .05), equivalent to six tablets per day of 5-mg hydrocodone. Those receiving adjuvant chemotherapy had modestly higher doses (P = .002), but patients with no chemotherapy still had doses equivalent to five tablets per day of 5-mg hydrocodone. Across different procedures, the covariate-adjusted risk of new persistent opioid use in patients receiving adjuvant chemotherapy was 15% to 21%, compared with 7% to 11% for those with no chemotherapy.ConclusionNew persistent opioid use is a common iatrogenic complication in patients with cancer undergoing curative-intent surgery. This problem requires changes to prescribing guidelines and patient counseling during the surveillance and survivorship phases of care.

    更新日期:2017-10-20
  • Safety and Efficacy Implications of Discontinuing Combination Ipilimumab and Nivolumab in Advanced Melanoma
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-19
    Matteo S. Carlino; Shahneen Sandhu

    The advent of antibodies that block the immune checkpoints, cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1), have dramatically changed the therapeutic paradigm for melanoma.1-4 Ipilimumab, an anti-CTLA-4 antibody, was the first systemic therapy to improve overall survival (OS) in patients with advanced melanoma.1 Nivolumab and pembrolizumab, anti-PD-1 antibodies, were subsequently found to be superior to ipilimumab.2,3 Collectively, these checkpoint inhibitors result in durable responses and are now the mainstay of advanced melanoma management.1-4 Consistent with the immune-activating mechanism of these agents, induction of autoimmunity against multiple organ systems is common. Although these immune-related adverse events (irAEs) largely are manageable, they can be potentially life threatening.

    更新日期:2017-10-20
  • Neurocognitive Functioning in the AALL0232 Protocol
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-18
    Ian Joseph Cohen

    I would like to congratulate Hardy et al1 on their report in Journal of Clinical Oncology analyzing the dangers of neurocognitive functioning in children with high-risk acute lymphoblastic leukemia (ALL) treated on the AALL0213 protocol. This report complements the neurotoxicity data provided in the article by Larsen et al,2 which discussed only seizures and strokes. Hardy et al report that increasing leucovorin (folinic acid) rescue reduced the frequency of toxicity after lower doses of methotrexate (MTX) and that early high-dose leucovorin after MTX 33.6 gm/m2 resulted in little acute or chronic neurotoxicity; however, the authors did not suggest an explanation for why they found no significant difference in neurocognitive outcome among patients who received high-dose MTX and leucovorin rescue versus those who received escalating doses of MTX and PEG asparaginase.

    更新日期:2017-10-19
  • Reply to I.J. Cohen
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-18
    Kristina K. Hardy; Leanne M. Embry; John A. Kairalla; Shanjun Helian; Meenakshi Devidas; F. Daniel Armstrong; Stephen Hunger; William L. Carroll; Eric Larsen; Elizabeth A. Raetz; Mignon L. Loh; Wenjian Yang; Mary V. Relling; Robert B. Noll; Naomi Winick

    The overarching goal of pediatric oncologists is to cure while minimizing the likelihood of serious acute and long-term toxicities. To this end, the dramatic improvement in survival for patients with acute lymphoblastic leukemia (ALL) over the past 30 years is attributable to an enhanced understanding of leukemia biology and the development of a robust risk classification system designed to limit treatment intensity for those with an excellent prognosis when treated with standard therapies.

    更新日期:2017-10-19
  • Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-17
    Margaret K. Callahan; Harriet Kluger; Michael A. Postow; Neil H. Segal; Alexander Lesokhin; Michael B. Atkins; John M. Kirkwood; Suba Krishnan; Rafia Bhore; Christine Horak; Jedd D. Wolchok; Mario Sznol

    Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

    更新日期:2017-10-17
  • Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti–T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease–Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-17
    Robert J. Soiffer; Haesook T. Kim; Joseph McGuirk; Mitchell E. Horwitz; Laura Johnston; Mrinal M. Patnaik; Witold Rybka; Andrew Artz; David L. Porter; Thomas C. Shea; Michael W. Boyer; Richard T. Maziarz; Paul J. Shaughnessy; Usama Gergis; Hana Safah; Ran Reshef; John F. DiPersio; Patrick J. Stiff; Madhuri Vusirikala; Jeff Szer; Jennifer Holter; James D. Levine; Paul J. Martin; Joseph A. Pidala; Ian D. Lewis; Vincent T. Ho; Edwin P. Alyea; Jerome Ritz; Frank Glavin; Peter Westervelt; Madan H. Jagasia; Yi-Bin Chen

    Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti–T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days −3, −2, −1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [P = .04] and 59% v 74% [P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

    更新日期:2017-10-17
  • Factors That Contributed to Black-White Disparities in Survival Among Nonelderly Women With Breast Cancer Between 2004 and 2013
    J. Clin. Oncol. (IF 24.008) Pub Date : 2017-10-16
    Ahmedin Jemal; Anthony S. Robbins; Chun Chieh Lin; W. Dana Flanders; Carol E. DeSantis; Elizabeth M. Ward; Rachel A. Freedman

    Purpose To estimate the contribution of differences in demographics, comorbidity, insurance, tumor characteristics, and treatment to the overall mortality disparity between nonelderly black and white women diagnosed with early-stage breast cancer. Patients and Methods Excess relative risk of all-cause death in black versus white women diagnosed with stage I to III breast cancer, expressed as a percentage and stratified by hormone receptor status for each variable (demographics, comorbidity, insurance, tumor characteristics, and treatment) in sequentially, propensity-scored, optimally matched patients by using multivariable hazard ratios (HRs). Results We identified 563,497 white and black women 18 to 64 years of age diagnosed with stage I to III breast cancer from 2004 to 2013 in the National Cancer Data Base. Among women with hormone receptor–positive disease, who represented 78.5% of all patients, the HR for death in black versus white women in the demographics-matched model was 2.05 (95% CI, 1.94 to 2.17). The HR decreased to 1.93 (95% CI, 1.83 to 2.04), 1.54 (95% CI, 1.47 to 1.62), 1.30 (95% CI, 1.24 to 1.36), and 1.25 (95% CI, 1.19 to 1.31) when sequentially matched for comorbidity, insurance, tumor characteristics, and treatment, respectively. These factors combined accounted for 76.3% of the total excess risk of death in black patients; insurance accounted for 37.0% of the total excess, followed by tumor characteristics (23.2%), comorbidities (11.3%), and treatment (4.8%). Results generally were similar among women with hormone receptor–negative disease, although the HRs were substantially smaller. Conclusion Matching by insurance explained one third of the excess risk of death among nonelderly black versus white women diagnosed with early-stage breast cancer; matching by tumor characteristics explained approximately one fifth of the excess risk. Efforts to focus on equalization of access to care could substantially reduce ethnic/racial disparities in overall survival among nonelderly women diagnosed with breast cancer.

    更新日期:2017-10-17
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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